* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With hydrazine hydrate In methanol at 20℃; for 0.5 h; Cooling with ice
Hydrazine hydrate (3.62 mL, 48.53 mmol) was added dropwise to a cooled (ice bath) solution of methyl propiolate (4.23 mL, 47.58 mmol) in methanol (40 mL). The reaction was allowed to stir for 30 min at room temperature. Brine (10 mL) was added and then the methanol was removed under vacuum. The remaining aqueous layer was extracted with EtOAc (4.x.75 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield the title compound (44, 3.82 g, 95percent) as a cream solid; δH (400 MHz, DMSO): 5.44 (1H, d, J 2.27 Hz), 7.35 (1H, d, J 2.23 Hz), 9.50 (1H, br s, NH), 11.45 (1H, br s, NH); δC (101 MHz, DMSO): 89.25, 129.71, 160.73; m/z (ES+) 85.04 (100, MH+); HRMS (ESI): MH+, found 85.03951. C3H5N2O requires 85.03964.
66%
With hydrazine hydrate In methanol at 0 - 25℃; for 0.5 h;
To a solution of methyl prop-2-ynoate (150 g, 1785.7 mmol) in MeOH (1500 mL) was added hydrazine hydrate (89.2 g, 1784.0 mmol) dropwise at 0° C. The reaction was stirred at r.t. for 30 min. Saturated aqueous sodium chloride (400 mL) was added, and then methanol was removed under vacuum. The aqueous layer was extracted with EtOAc (3×500 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 1,2-dihydropyrazol-3-one (99.5 g, 66percent) as a white solid. m/z: ES+[M+H]+ 85.
62%
With hydrazine hydrate In methanol at 20℃; for 0.5 h; Cooling with ice
The compound of hydrazine monohydrate (85percent, 4.81g, 95.2mrnol) was added dropwise to a cooled (ice bath) solution of 92 (8g, 96.2mmol) in methanol (5OmL). The reaction was allowed to stir for 30 minutes at room temperature, then, the solvent was removed under vacuo. Theremaining aqueous layer was extracted with Et0Ac(5mL5) and the combined organic layerswere dried (MgSO4), filtered and concentrated in vacuo to yield the title product 93 (5g, yield:62?/o)1HNIS’iR (400 MHz, DMSO.-d6): ö5.40 (s, 2H), 7.32 (s, 2 H).
With chloro-trimethyl-silane; NaH; hydrazine hydrate In tetrahydrofuran; methanol; ethanol; acetic acid methyl ester
(a) Preparation of the 3-(1-methyl-1H-indazol-3-yl)-2-pyrazolin-5-one, (VIj) A mixture of indazole-3-carboxylic acid (5 g, 31 mmol), chlorotrimethylsilane (34 g, 310 mmol), and methanol (50 mL) was allowed to stir overnight. The solvent was evaporated to obtain a yellow product (4 g, 74percent yield). A slurry of the methyl ester (4 g, 23 mmol), NaH (1.3 g, 35 mmol), iodomethane (33 g, 230 mmol), and THF (60 mL) was mixed overnight. The mixture was neutralized and extracted with ethyl acetate. The desired product (IIId) was collected as a yellow solid (4 g, 21 mmol). A slurry of the ester (IIId) (4 g, 21 mmol), NaH (1.2 g, 32 mmol), and methyl acetate (40 mL) was refluxed for four hours. The mixture was neutralized with acetic acid and the product was extracted with ethyl acetate, concentrated in vacuo to provide the desired β-ketoester, ethyl 3-(1-methyl(1H-indazol-3-yl))-3-oxopropanoate, (Ve) as an orange gum (4.6 g). A mixture of β-ketoester (Ve) (4.6 g, 20 mmol), hydrazine hydrate (0.77 g, 24 mmol), and ethanol (10 mL) was refluxed overnight. The resulting precipitate was filtered to obtain the pyrazolone (VIj) as a white solid (1.2 g, 30percent yield).
Reference：
[1] Patent: US6455525, 2002, B1,
3
[ 66224-70-2 ]
[ 137-45-1 ]
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1987, vol. 57, # 2, p. 409 - 411[2] Zhurnal Obshchei Khimii, 1987, vol. 57, # 2, p. 468 - 471
4
[ 547-64-8 ]
[ 99644-87-8 ]
[ 137-45-1 ]
Reference：
[1] Patent: US2003/60467, 2003, A1,
5
[ 1646-26-0 ]
[ 105-58-8 ]
[ 137-45-1 ]
Reference：
[1] Patent: US6455525, 2002, B1,
6
[ 69128-14-9 ]
[ 554-00-7 ]
[ 137-45-1 ]
Reference：
[1] Patent: US4113954, 1978, A,
7
[ 5329-12-4 ]
[ 100-01-6 ]
[ 137-45-1 ]
Reference：
[1] Patent: US4113954, 1978, A,
8
[ 16205-84-8 ]
[ 137-45-1 ]
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1987, vol. 57, # 2, p. 409 - 411[2] Zhurnal Obshchei Khimii, 1987, vol. 57, # 2, p. 468 - 471
9
[ 66-22-8 ]
[ 137-45-1 ]
[ 57-13-6 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1924, vol. 178, p. 812
10
[ 58-96-8 ]
[ 137-45-1 ]
Reference：
[1] Journal of Biological Chemistry, 1926, vol. 71, p. 170
11
[ 108-24-7 ]
[ 137-45-1 ]
[ 852471-15-9 ]
Yield
Reaction Conditions
Operation in experiment
93%
at 95℃; for 3 h;
A 100 mL round bottom flask equipped with a stir bar and a condenser was charged with lH-pyrazol-5-ol (4.97 g, 59.11 mmol) and pyridine (25 mL, 309.1 mmol). The mixture was stirred at 95 °C. A solution of acetic anhydride (5.6 mL, 59.35 mmol) in pyridine (10 mL, 123.6 mmol) was added dropwise over a period of 3 minutes. The mixture was then stirred at 95 °C for an additional three hours. The solvents were removed under reduced pressure. The solid residue was triturated in 40 mL of diethyl ether, filtered, washed with diethyl ether and dried to give l-(3-hydroxypyrazol-l-yl)ethanone (6.96 g, 93percent) . 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, IH), 8.13 (d, J = 3.0 Hz, IH), 6.01 (d, J = 3.0 Hz, IH), 2.48 (s, 3H).
84%
at 95℃; for 1.25 h;
1.2 1 -Acetyl-3-hydroxy-1 H-pyrazoleA solution of 3-hydroxy-1 H-pyrazole (8.2 g, 97.5 mmol) in pyridine (40 mL) was heated to 95°C. A mixture consisting of acetic anhydride (9.4 mL, 102 mmol) and pyridine (20 mL) was added over 15 min; then stirring at 95°C was continued for 60 min. All volatiles were then removed under reduced pressure and to the residue was added 200 mL of diethyl ether. The slurry was stirred overnight at room temperature, then the solid was filtered off and rinsed with diethyl ether. The product was obtained as an off- white solid (10.3 g, 81.7 mmol, 84percent yield).H NMR (DMSO-de, 500 MHz): δ (ppm) = 10.95 (s, 1 H); 8.13 (d, J = 3.0 Hz, 1 H); 6.00 (d, J = 3.0 Hz, 1 H), 2.48 (s, 3 H).3C NMR (DMSO-de, 125 MHz): δ (ppm) = 167.9; 163.9; 129.8; 99.8; 21 .3.Melting point: 191 °C.
1.5 g
at 25℃; for 2 h;
Reference Production Example 2 (0551) A mixture of 3.00 g of 1H-pyrazol-3-ol mentioned in Reference Production Example 1, 3.1 mL of acetic anhydride, and 90 mL of acetic acid was stirred at 25° C. for 2 hours. (0552) Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated sodium bicarbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 1.50 g of 1-acetyl-1H-pyrazol-3-ol. 1-Acetyl-1H-pyrazol-3-ol (0553) (0554) 1H-NMR (DMSO-d6) δ (ppm): 11.04 (1H, s), 8.14 (1H, dd, J=2.9, 1.0 Hz), 6.02 (1H, dd, J=2.9, 1.0 Hz), 2.49 (3H, s).
1.50 g
at 25℃; for 2 h;
The 1H- pyrazol-3-ol 3.00g of (mentioned in Reference Preparation Example 1), 3.1mL of a mixture of acetic anhydride and acetic acid 90mL was stirred at 25 2 hours. Water was poured into the reaction mixture and the mixture and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 1.50g of 1-acetyl--1H- pyrazol-3-ol.
The compound im-8-a (2.85 g, 0.034 mol) was dissolved in pyridine (6 mL), cooled to 0 ° C., acetic anhydride (3.36 mL, 0.036 mol) And the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed, diethyl ether (30 mL) was added, and the mixture was stirred at room temperature for 16 hours. The resulting solid was filtered and dried to give the title compound im-8 (3.24 g, 76percent) as a yellow solid.
The process of Example II is followed except that 500 ml. of toluene solvent is included to the charge in step A. The resulting pyrazolone is obtained in about 60% yield.
This reaction was repeated on larger scale (0.03 mole) with similar results (85% yield). The reduction step required 0.20 mole of ammonium formate with heating at 50 for 30 min. A solution of diester 4 (6.5 g, 0.02 mole) and p-nitrophenylisothiocyanate (4.3 g, 0.024 mole) in THF (60 ml) in a three-neck flask fitted with thermometer, nitrogen inlet, and magnetic stir bar was cooled to -50 with a dry ice/isopropanol bath. Potassium t-butoxide (2.6 g, 0.023 mole) was added to the mixture before allowing it to warm slowly to about 10. ?The deep red color initially present faded to a yellow-orange color as the reaction progressed. The course of the reaction could also be followed by TLC (silica gel) using 2:1 heptane:ethyl acetate (plus a little acetic acid to reduce streaking) as eluent. The thioamide product is yellow, is less mobile than either starting material, and couples slowly with Dox to give an orange[dye.] Ice (50 g), 1 N NaHCO3 (30 ml), water (100 ml), and heptane (150 ml) were then added to the mixture before stirring vigorously. The orange aqueous layer was separated and treated with 30 ml of 12 N HCl to precipitate the product as a gum which could be induced to crystallize by the addition of diethyl ether. A total of 8.2 g (81%) of adduct 5 was obtained. Subsequent experiments showed that this reaction proceeded equally well using DMF as solvent with molecular sieves present to absorb water at a preparatively more practical reaction temperature of 0. Bases such as sodium methoxide or potassium carbonate also worked but the reaction was generally slower. Trichlorophenylhydrazine (4.65 g, 0.022 mole) and adduct 5 (10.67 g, 0.021 mole) were combined in 100 ml of THF and cooled to 10 before adding dicyclohexylcarbodiimide (4.5 g, 0.022 mole), warming to room temperature, and stirring for 30 min. The hydrazone intermediate was converted to pyrazolone by addition of 1,8-diazabicylo[5.4.0]undec-7-ene (DBU, 3.2 g, 0.021 mole) to the mixture and stirring for 10 min.
EXAMPLE 3 Preparation of pyrazolone from N'-(3-dimethylaminopropyl)-sulfanilamide having the structure: STR14 A solution of 0.2 g mole (51.5 g) of the intermediate prepared as in Example 1 in 215 mL water, is iced to 0 C., and stirred in an ice bath. Hydrochloric acid (95 mL, 37%) is added followed by a solution of 14 g of sodium nitrite. After stirring for ten minutes with a slight excess of nitrite present, the excess is removed with sulfamic acid. The diazonium salt solution is neutralized to pH 6 by sifting in 28 g of sodium bicarbonate at 0 C. During 15 minutes, 25.2 g of sodium sulfate is sifted in, and the pH rises to 9.4. To the bright orange colored solution, after 30 minutes and at <5 C., is added 22 g sodium bisulfite during 10 minutes. The solution is pale yellow and diazo nearly disappears. Colorless crystalline precipitate begins to form. The reaction is then stirred an additional two hours, heated to 75 C. and 70 g 37% hydrochloric acid is added. The temperature is increased to 90-95 C. and held for four hours with sulfur dioxide evolving. The solution is stirred and cooled overnight. Sodium hydroxide (55 g, 50%) is added to pH 6. Ethyl acetoacetate (26 g; 0.2 mole) is added at 35 C. Heating to the boiling point, and acidification with hydrochloric acid (20 mL) gives a yellow tarry precipitate.
EXAMPLE 1 Synthesis of a Pyrazolone 10.0 Grams (67 mmols) of a 2,3-dichloropropionic acid amide and 100 g of a tetrahydrofuran were fed into a 200-ml four neck flask, followed by the dropwise addition of 10.1 g (202mmols) of a hydrated hydrazine over a period of 20 minutes in a water bath maintained at 15 C. with stirring. The temperature was then raised to 50 C., and the reaction was finished after stirred for one hour. 100 Grams of the tetrahydrofuran was added-to the reaction product that was obtained by condensing and drying the reaction solution, and the mixture was stirred at room temperature. After insoluble matters were separated by filtration, the tetrahydrofuran solution of the product was analyzed by gas chromatography to find that a pyrazolone was contained in an amount of 5.3 g. The yield of the pyrazolone was 94 mol % on the basis of the 2,3-dichloropropionic acid amide. The tetrahydrofuran solution of the above product was condensed and dried again, and was recrystallized with water to obtain white crystals of the pyrazolone, m.p. 162 to 164 C. (165 C. according to the literature).
The following pyrazolone dyestuffs are obtained completely analogously:
Step 2 Preparation of the pyrazolone of Formula I. 17 g Hydrazinoester of step 1, 8.1 g 4-aminoacetanilide and 10 ml glacial acetic acid were heated for 2.[. hours on a boiling water bath, the reaction mixture while hot stirred with 50 ml methanol and then cooled. The precipitated product was drawn off and washed with methanol. This represents pyrazolone in a relatively pure form. Yield: 16.3 g, i.e. 80% of the theoretical F. 149-153C
Examples of such compounds are the following: ... 4-(2-chloro-phenylhydrazono)-1-phenyl-3-methyl-4,5-dihydro-5-pyrazolone 4-phenylhydrazone-1-(4-sulfo-phenyl)-3-methyl-4,5-dihydro-5-pyrazolone 4-(2-chloro-phenylhydrazono)-1-(2-chloro-phenyl)-3-methyl-4,5-dihydro-5-pyrazolone 4-(2-sulfo-phenylhydrazono)-1-(2-chloro-phenyl)-3-methyl-4,5-dihydro-5-pyrazolone -dihydro-5-pyrazolone 4-(2-hydroxy-4-nitro-5-methylsulfonyl-phenylhydrazono)-3-methyl-4,5-dihydro-1-phenyl-5-pyrazolone 4-(2-hydroxy-3-nitro-5-tert-amyl-phenylhydrazono)-3 -methyl-1-phenyl-4,5-dihydro-5-pyrazolone 4-(2-hydroxy-4-nitro-phenylhydrazono)-3-methyl-1-phenyl-4,5-dihydro-5-pyrazolone.
a. Preparation of 2-(4-chloro-2-fluorophenyl)-1,4,5,6-tetrahydrocyclopentapyrazol-3(2H)-one 7.5 Parts of 4-chloro-2-fluorophenylhydrazine and 6.6 parts of methyl 2-oxocyclopentanecarboxylate (purchased from Aldrich Chemical Company) were dissolved in 200 parts toluene. The reactants were heated at reflux for 1-2 hours removing water that was formed. The reaction mixture was cooled to 100 C., and a solution of 5.0 parts of sodium methoxide dissolved in 25 parts methanol was added dropwise, removing methanol as its azeotrope with toluene. The reaction mixture was heated until the internal temperature reached 110. The reaction was then cooled and poured into 200 parts ice water. The organic layer was separated, and the aqueous layer was washed twice with diethyl ether. Cold, dilute hydrochloric acid was added, with stirring, to the aqueous layer until pH 2 was reached. The resulting oily product solidified and was filtered, dried and recrystallized from acetonitrile to yield 3.3 parts of tan crystalline material, m.p. 157-160. Alternatively, the above pyrazolone was prepared by the following procedure.
EXAMPLE 4 Preparation of 3-bromo-2-(4-Chloro-2-fluorophenyl)-2,4,5,6-tetrahydrocyclopentapyrazole 7.5 parts of 4-chloro-2-fluorophenylhydrazine and 6.6 parts of methyl 2-oxocyclopentanecarboxylate (purchased from Aldrich Chemical Company) were dissolved in 200 parts toluene. The reactants were heated at reflux for 1-2 hours. Water was removed as formed. The reaction mixture was cooled to 100, and a solution of 5.0 parts of sodium methoxide dissolved in 25 parts of methanol was added dropwise, removing methanol as its azeotrope with toluene. The reaction mixture was heated until the internal temperature attained 110. After cooling, the product was poured into 200 parts of ice water. The organic layer was separated, and the aqueous layer was wished twice with diethyl ether. Cold, dilute hydrochloric acid was added, with stirring to the aqueous layer until pH was attained. The resulting oily product solidified and was filtered, dried and recrystallized from acetonitrile to yield 3.3 parts of tan crystalline material, m.p. 157-160. Alternatively, the above pyrazolone was prepared by the following procedure.
EXAMPLE I A diazonium salt solution was made by adding 31 g. of ice to a mixture of 46.9 g. (39.6 ml) of 32% HCl and 30 ml glacial HAc and dissolving 16.1 g. orthoaminobenzotrifluoride in the iced mixture; thereafter 25 ml 4N NaNO2 solution was added while holding the temperature below 0 C. and the diazonium salt solution was stirred for 45 minutes after the last addition of sodium nitrite before coupling with the pyrazolone prepared as follows: 40 grams Na2 CO3 was dissolved in 200 ml water, and 23.2 g. of 1-(phenyl-3-carbethoxy-5-pyrazolone was added.
With pyridine; hydrogenchloride; sodium hydroxide; chloro-trimethyl-silane; hydrazine hydrate; In diethyl ether; ethanol; water;
a Toluene-4-sulfonic Acid 4-cyclopentyl-5-(1-hydroxyethyl)-1H-pyrazol-3-yl Ester To a solution of methyl lactate (6.9 g, 66.5 mmol) and pyridine (5.9 ml, 1.1 molar eq) in diethyl ether (200 ml) at 0 C. was added dropwise over 1 h 2-bromo-2-cyclopentylacetyl chloride (15 g, 1 molar eq). The reaction mixture was allowed to warm to room temperature and stirred for 14 h. The solution was washed with water (1*100 ml) and brine (1*100 ml), then dried (Na2SO4), filtered and concentrated in vacuo to leave an oil (18.7 g). This oil was dissolved in a solution of diethyl ether (56 ml) and trimethylsilyl chloride (224 ml) in the presence of zinc (18.33 g, 5 molar eq) and heated under reflux for 1 h with rapid stirring. After this time, the reaction mixture was cooled in an ice bath and water (200 ml) was added slowly and cautiously with rapid stirring. Then 4 N sodium hydroxide solution was added carefully until a pH of 14 was achieved and the aqueous layer was separated and washed with diethyl ether (1*200 ml). The aqueous layer was then acidified to pH 1 using conc. HCl and was extracted with dichloromethane (4*200 ml). The combined layers were dried (Na2SO4), filtered and evaporated under vacuum to give a crude tetronic acid (3.48 g). This was dissolved in ethanol (80 ml) and after the addition of hydrazine hydrate (1.9 ml, 2 molar eq) the reaction mixture was heated under reflux for 14 h. The solvents were removed by rotary evaporation under high vacuum to leave a crude pyrazolone (3.4 g).
(5Hydroxy-1H-pyrazol-4-ylmethylene)-dimethylammonium Chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.5%
In N-methyl-acetamide;
Example 7 Preparation of (5Hydroxy-1H-pyrazol-4-ylmethylene)-dimethylammonium Chloride A cold solution of 21 g <strong>[137-45-1]<strong>[137-45-1]1,2-dihydropyrazol-3-on</strong>e</strong> (0.125 mol) in 50 ml anhydrous dimethylformamide was treated with 40 g phosphorous oxythiochloride (0.15 mol) over 1 h period at a temperature at or below 20 C. The reaction mixture was warmed to room temperature and then heated to 90-95 C. and held for 1 h. The thick slurry was cooled in an ice bath and diluted with 80 ml absolute ethanol keeping the temperature below 0 C. After stirring for 4 h, the product crystallized in white solids. After filtration and drying in a vacuum, the product of melting point 234 C. was obtained in 76.5% yield.
With triethylamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
Step 2 4-tert-Butyl-5-hydroxymethyl-3-[(4-methylphenyl)sulphonyloxy]pyrazole To a suspension of the pyrazolone (7.2 g, 42 mmol) in DCM (140 mL) was added 4-toluene sulphonyl chloride (9.7 g, 51 mmol) followed by Et3N (7.7 mL, 55 mmol) dropwise. The mixture was stirred at room temperature for 16h. The mixture was washed with brine (150 mL) and dried (Na2SO4) and evaporated. The residue was chromatographed on silica with 5 to 10% MeOH/DCM to afford the title compound (9.3 g, 68%) as a cream solid. mp. 62-65 C. 1H NMR (400MHz, d6-DMSO) delta1.28 (9H, s), 2.43 (3H, s), 4.49 (2H, d, J=5.2 Hz), 5.32 (1H, t, J=5.2 Hz), 7.48 (2,d, J=8.2 Hz), 7.86 (2H, d, J=8.2 Hz), 12.28 (1H, s). MS (ES+) 325 (M+1).
3-chloromethyl-1-methyl-1H-[1,2,4]triazole hydrochloride[ No CAS ]
[ 342652-75-9 ]
Yield
Reaction Conditions
Operation in experiment
33%
With potassium carbonate; In N,N-dimethyl-formamide;
Step 2 5-Hydroxymethyl-3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-4-phenylpyrazole To a solution of the pyrazolone (1.2 g, 6.3 mmol) in DMF (20 mL) was added finely ground K2CO3 (5.23 g, 39 mmol) and 3-chloromethyl-1-methyl-1H[1,2,4]triazole hydrochloride (1.06 g, 6.3 mmol) and the reaction mixture was heated at 50 C. for 6h. After cooling the mixture was filtered and the filtrate evaporated. The residue was chromatographed on silica eluding with 10% MeOH/DCM to afford the title compound (0.60 g, 33%) as a colourless foam. 1H NMR (400 MHz, d6-DMSO) delta4.00 (3H, s), 4.63 (2H, d, J=5.2 Hz), 5.35 (2H, s), 5.55 (1H, t, J=5.2 Hz), 7.32 (1H, t, J=7.3 Hz), 7.43-7.51 (2H, m), 7.65 (2H, d, J=7.3 Hz), 8.58 (1H, s), 12.23 (1H, s). MS (ES+) 286 (M+1).
(a) Preparation of 3-pyrazin-2-yl-2-pyrazolin-5-one, (VIh) A slurry of ethyl pyrazine-2-carboxylate (10 g, 66 mmol), in methyl acetate (40 mL) and NaH (60% dispersion in mineral oil, 3.7 g, 97 mmol, 1.47 equiv.) was refluxed for an hour. The reaction mixture was cooled to room temperature, neutralized with acetic acid and extracted with ethyl acetate. The solvent was evaporation to yield the beta-ketoester (Vc) (6.35 g) as an off-white solid. [MS: 179, (M-H)]. A mixture of the ester (Vc) (0.5 g, 2.8 mmol), methyl hydrazine (0. 16 g, 3.4 mmol) in ethanol (3 mL) was refluxed overnight. The resulting precipitate was filtered to provide the pyrazolone (VIh) as an orange solid (0.3 g, 1.7 mmol).
Yield
Reaction Conditions
Operation in experiment
79%
(a) Preparation of 3-(3-thienyl)-2-pyrazolin-5-one (VIc) To a vigorously stirred suspension of NaH (60% dispersion in mineral oil, 830 mg, 20.3 mmol, 2.85 equiv.) and diethyl carbonate (1.7 mL, 14.04 mmol, 1.99 equiv.) in dry toluene (15 mL) was added drop wise (over a period of 1 h) a solution of the methyl ketone, 1-thiophen-3-yl-ethanone (900 mg., 7.14 mmol.) in toluene (5 mL) under reflux. After addition, the mixture was stirred at reflux for 0.5 h. The mixture was cooled to RT and was acidified with glacial acetic acid. After adding cold water, the mixture was extracted 3 times with ethyl acetate. Combined organic extract was washed with water and brine. After drying over MgSO4, solvent was evaporated to furnish the crude beta-ketoester, 3-Oxo-3-thiophen-3-yl-propionic acid ethyl. To the crude product was added absolute ethanol (5 mL) and hydrazine hydrate (0.5 mL). The mixture was kept under reflux for 4h. Solvent was evaporated in vacuo. The crude mass was purified by flash chromatography (EtOAc). The pyrazolone (Vic) was isolated as a solid (940 mg, 79%). 1H-NMR (DMSO-d6) delta 11.8 (br s, 1H), 9.7 (br s, 1H), 7.68 (d, J=1.98 Hz, 1H), 7.55 (m, 1H), 7.38 (d, J=4.92 Hz, 1H), 5.74 (s, 1H). MS: 167(M+H).
Yield
Reaction Conditions
Operation in experiment
The ester, (IIIc) was dissolved in anhydrous methyl acetate (4 mL) and solution purged with an inert atmosphere. To this yellow solution sodium hydride (60% dispersion in mineral oil, 0.53 g, 13.25 mmol) was added providing a light yellow precipitate. The reaction mixture was then heated to 65 C. and it turned to a light green precipitate. Additional methyl acetate (4 mL) was added and in ten minutes the reaction mixture became a tan solid. The reaction was removed from the heat and an additional methyl acetate (20 mL) was added. The mixture was neutralized with acetic acid. The solid was filtered off and the filtrate was evaporated. The solid from the filtrate was washed with ether to yield the desired beta-ketoester, ethyl 3-[5-(dimethylamino)(1,3,4-thiadiazol-2-yl)]-3-oxopropanoate, (Vd) (5.2 mmol) as a yellow solid. A mixture of the beta-ketoester (Vd) (1.2 g, 1.31 mmol), ethanol (2 mL) and hydrazine hydrate (0.063 g, 1.96 mmol) was heated to 65 C. for two hours. The precipitate was filtered to obtain the pyrazolone (VIi) (0.075 g, 0.36mmol) as a light yellow solid.
17
[ 110-89-4 ]
[ 137-45-1 ]
[ 2199-58-8 ]
4-[(3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazin-2-yl-2-pyrazolin-5-one[ No CAS ]
[ 324570-67-4 ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
(b) Preparation of Compound 74 A mixture of the pyrazolone (VIe) (50 mg, 0.30 mmol) and 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde, (42 mg, 0.34 mmol, 1.13 equiv.) in absolute ethanol (1 mL) along with 2-3 drops of piperidine was stirred at 80-90 C. for 4 h. The product that separated as a solid was filtered from hot reaction mixture, and washed with hot ethanol. After drying, 40 mg (50%) of compound (74) was isolated as a single geometrical isomer. 1H-NMR (DMSO-d6) delta 14.5 (br s, 1H), 12.10 (s, 1H), 9.14 (d, J=0.82 Hz, 1H), 8.71 (s, 1H), 7.67 (d, J=1.81 Hz, 1H), 8.58 (d, J=2.47 Hz, 1H), 6.24 (s, 1H), 2.36 (s, 3H), 2.25 (s, 3H). MS: 268 (M+H). HPLC: Rt=9.89 m.
3-benzo[d]furan-2-yl-4-[(3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
(b) Preparation of Compound (57) A mixture of the pyrazolone (VId) (75 mg, 0.375 mmol) and 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (50 mg, 0.40 mmol, 1.07 equiv.) in absolute ethanol (1 mL) along with 2-3 drops of piperidine was stirred at 80-90 C. for 4 h. The product that separated as a solid was filtered and washed (with ethanol). After drying, 105 mg (92%) of compound 57 was isolated as a single geometrical isomer. 1H-NMR (DMSO-d6) delta 14.5 (br s, 1H), 12.04 (br s, 1H), 7.93 (s, 1H), 7.67 (m, 2H), 7.36-7.24 (overlapping m & s, 3H),6.26 (s, 1H),2.37 (s, 3H), 2.33 (s, 3H). MS: 306 (M+H). HPLC: Rt=13.46 m.
4-[(3,5-dimethylpyrrol-2-yl)methylene]-3-(1,3-thiazol-2-yl)-2-pyrazolin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
Example 2 Preparation of 4-[(3,5-dimethylpyrrol-2-yl)methylene]-3-(1,3-thiazol-2-yl)-2 pyrazolin-5-one (Compound 26) A mixture of the pyrazolone (VIa) (50 mg, 0.30 mmol) and 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (40 mg, 0.32 mmol, 1.08 equiv.) in absolute ethanol (1 mL) along with 2-3 drops of piperidine was stirred at 80-90 C. for 4 h. The product that separated as a solid was filtered and washed with ethanol. After drying, 65 mg (74%) of compound 26 was isolated as a single geometrical isomer. 1H-NMR (DMSO-d6) delta14.39 (s, 1H), 12.01 (s, 1H), 8.70 (s, 1H), 7.95 (d, J=3.17 Hz, 1H), 7.74 (d, J=3.18 Hz, 1H), 6.26 (s, 1H), 2.36 (s, 3H), 2.27 (s, 3H). MS: 273 (M+H). HPLC: Rt=10.54 min.
4-[(3,5-dimethylpyrrol-2-yl)methylene]-3-(furan-2-yl)-2-pyrazolin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
(b) Preparation of Compound (28) A mixture of the pyrazolone (VIb) (50 mg, 0.33 mmol) 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (45 mg, 0.36 mmol, 1.09 equiv.) in absolute ethanol (1 mL) along with 2-3 drops of piperidine was stirred at 80-90 C. for 4h. The mixture was cooled (ice bath) and the product that separated as a solid was filtered and washed with cold methanol. After drying, 58 mg (69%) of compound 28 was isolated as a single geometrical isomer. 1H-NMR (DMSO-d6) delta 14.47 (s, 1H), 11.81 (s, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 6.86 (d, J=3.30 Hz, 1H), 6.61 (s, 1H), 6.22 (s, 1H), 2.35 (s, 3H), 2.27 (s, 3H). MS: 256 (M+H). HPLC: Rt=10.51 m.
4-[(3,5-dimethylpyrrol-2-yl)methylene]-3-(thien-3-yl)-2-pyrazolin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
(b) Preparation of Compound (37) A mixture of the pyrazolone (VIc) (50 mg, 0.30 mmol) 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (41 mg, 0.33 mmol, 1.11 equiv.) in absolute ethanol (1 mL) along with 2-3 drops of piperidine was stirred at 80-90 C. for 3 h. The product that separated as a solid was filtered and washed with ethanol. After drying, 64 mg (79%) of the compound 37 was isolated as a single geometrical isomer. 1H-NMR (DMSO-d6) delta 14.44 (br s, 1H), 11.68 (s, 1H), 7.89 (d, J=1.60 Hz, 1H), 7.64 (m, 1H), 7.46 (s, 1H), 7.38 (m, 1H), 6.18 (s, 1H), 2.34 (s, 3H), 2.23 (s, 3H). MS: 272 (M+H). HPLC: Rt=10.75 m.
(b) Preparation of Compound 118 A mixture of the pyrazolone (VIg) (50 mg, 0.17 mmol), indole-3-carboxaldehyde (30 mg, 0.19 mmol) in absolute ethanol (1 mL) along with 2-3 drops of piperidine was stirred at 80-90 C. for 3 h. The product that separated as a solid was filtered and washed with ethanol. After drying, 52 mg of the compound 118 was isolated as a single geometrical isomer.
4-(indol-3-ylmethylene)-3-(1,3-thiazol-2-yl)-2-pyrazolin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65 mg (74%)
In ethanol;
(b) Preparation of Compound 25 A mixture of the pyrazolone (VIa) (50 mg, 0.30 mmol) and indole-3-carboxaldehyde (47 mg, 0.32 mmol, 1.08 equiv.) in absolute ethanol (1 mL) along with 2-3 drops of piperidine was stirred at 80-90 C. for 4 h. The solid was filtered and washed with ethanol, dried under vacuo to provide 65 mg (74%) of compound 25 as a single geometrical isomer. 1H-NMR (DMSO-d6) delta11.85 (s, 1H), 9.83 (s, 1H), 9.42 (s, 1H), 8.05 (d, J=3.17 Hz, 1H), 7.80 (m, 2H), 7.58 (m, 1H), 7.30 (m, 3H). MS: 295 (M+H). HPLC: Rt=10.10 min.
3-(furan-2-yl)-4-(indol-3-ylmethylene)-2-pyrazolin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
Example 4 Preparation of 3-(2-furyl)-4-(indol-3-ylmethylene)-2-pyrazolin-5-one (Compound 29) A mixture of the pyrazolone (VIb) (50 mg, 0.33 mmol) and indole-3-carboxaldehyde, (53 mg, 0.36 mmol, 1.09 equiv.) in absolute ethanol (1 mL) along with 2-3 drops of piperidine was stirred at 80-90 C. for 4 h. The mixture was cooled in ice bath, and the product filtered and washed with cold methanol. After drying, 36 mg (40%) of compound 29 was isolated as a single geometrical isomer. 1H-NMR (DMSO-d6) delta 12.55 (br s, 1H), 11.62 (s, 1H), 9.82 (s, 1H), 8.45 (s, 1H), 7.89 (m, 2H), 7.56 (m, 1H), 7.28 (m, 2H), 6.96 (m, 1H), 6.66 (m, 1H). MS: 278 (M+H). HPLC: Rt=9.80 m.
4-[(4-chloro-1-methylindol-3-yl)methylene]-3-pyrazin-2-yl-2-pyrazolin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
(b) Preparation of Compound 189 A mixture of the pyrazolone (VIh) (0.035 g, 0.2 mmol), piperidine (0.01 mmol), ethanol (1 mL), and 4-chloro-1-methylindole-3-carboxaldehyde (0.046g, 0.24 mmol) was refluxed. The resulting precipitates were filtered to obtain compound 189 as a bright orange solid (0.036 g, 0.10 mmol).
4-[(1-methyl-4-phenylindol-3-yl)methylene]3-pyrazin-2-yl-2-pyrazolin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
(b) Preparation of Compound 202 A mixture of the pyrazolone (VIe) (40 mg, 0.24 mmol), 4-phenyl-1-methyl-indole-3-carboxaldehyde (84 mg, 0.35 mmol) in absolute ethanol (2 mL) along with 2-3 drops of piperidine was stirred at 80-90 C. for 2 h. The product that separated as a solid was filtered and washed with ethanol. After drying, 81 mg of the compound 202 was isolated as a single geometrical isomer.
(b) Preparation of Compound 205 A mixture of the pyrazolone (VIj) (0.043 g, 0.2 mmol), 4-bromo-1-methylindole-3-carboxaldehyde (0.052 g, 0.22 mmol), piperidine (0.01 mmol) and ethanol (1 mL was refluxed for 3.5 h. The resulting precipitate was filtered to obtain a bright orange solid (0.052 g, 60% yield).
With chloro-trimethyl-silane; NaH; hydrazine hydrate; In tetrahydrofuran; methanol; ethanol; acetic acid methyl ester;
(a) Preparation of the 3-(1-methyl-1H-indazol-3-yl)-2-pyrazolin-5-one, (VIj) A mixture of indazole-3-carboxylic acid (5 g, 31 mmol), chlorotrimethylsilane (34 g, 310 mmol), and methanol (50 mL) was allowed to stir overnight. The solvent was evaporated to obtain a yellow product (4 g, 74% yield). A slurry of the methyl ester (4 g, 23 mmol), NaH (1.3 g, 35 mmol), iodomethane (33 g, 230 mmol), and THF (60 mL) was mixed overnight. The mixture was neutralized and extracted with ethyl acetate. The desired product (IIId) was collected as a yellow solid (4 g, 21 mmol). A slurry of the ester (IIId) (4 g, 21 mmol), NaH (1.2 g, 32 mmol), and methyl acetate (40 mL) was refluxed for four hours. The mixture was neutralized with acetic acid and the product was extracted with ethyl acetate, concentrated in vacuo to provide the desired beta-ketoester, ethyl 3-(1-methyl(1H-indazol-3-yl))-3-oxopropanoate, (Ve) as an orange gum (4.6 g). A mixture of beta-ketoester (Ve) (4.6 g, 20 mmol), hydrazine hydrate (0.77 g, 24 mmol), and ethanol (10 mL) was refluxed overnight. The resulting precipitate was filtered to obtain the pyrazolone (VIj) as a white solid (1.2 g, 30% yield).
Example 20 Preparation of 4-[(dimethylamino)methylene]-3-(1.3-thiazol-2-yl)-2-pyrazolin-5-one, (Compound 296) To a solution of the pyrazolone (VIa), (250 mg, 1.5 mmol) in dry THF (12 mL) was added N,N-dimethylformamide di-tert-butyl acetal (0.319 g, 1.05 equiv) and the reaction mixture was heated under reflux for 15 min. TLC (10% methanol-chloroform) showed complete conversion of the pyrazolone (Rf=0.08) to a new product (Rf=0.17). Concentration of the reaction gave compound 296 as a solid. 1H-HMR (d6-DMSO) delta11.26 (s, 1H, enolic), 8.69 (s, 1H, =CH), 7.86 (s, 1H), 7.67 (s, 1H), 3.79 (s, 3H), 3.33 (s, 3H); electrospray MS, m/z 223 [M+1]+base peak; HPLC Rt=5.01 min. versus Rt=4.06 min. for the pyrazolone (VIa), (method A).
(b) Preparation of Compound 190 A mixture of the pyrazolone (VIi) (0.035 g, 0. 166mmol), 1-methyl indole-3-carboxaldehyde (0.032 g, 0.2 mmol) and ethanol (1 mL) was heated to 65 C. and stirred overnight. The orange precipitate that formed was filtered to obtain compound 190 (0.024 g, 0.068 mmol).
With NaH; hydrazine hydrate; In ethanol; toluene; mineral oil;
(a) Preparation of 3-benzo[d]furan-2-yl-2-pyrazolin-5-one (VId) To a vigorously stirred suspension of NaH (60% dispersion in mineral oil, 2.6 g, 65 mmol, 3.32 equiv.) and diethyl carbonate (4.7 mL, 38.83 mmol, 1.99 equiv.) in dry toluene (30 mL) was added drop wise (over a period of 1 h) a solution of the methyl ketone, 1-benzofuran-2-yl-ethanone (1 g, 7.87 mmol) in toluene (5 mL) under reflux. After addition, the mixture was stirred at reflux for 0.5 h. The mixture was cooled to RT and was acidified with glacial acetic acid. After adding cold water, the mixture was extracted 3 times with ethyl acetate. Combined organic extract was washed with water and brine. After drying over MgSO4, solvent was evaporated to furnish the crude betaketoester, 3-benzofuran-2-yl-3-oxo-propionic acid ethyl ester. To the crude product was added absolute ethanol (10 mL) and hydrazine hydrate (1.5 mL, excess). The mixture was kept under reflux for 4 h. A solid separated, which was filtered and washed with EtOH. Upon drying, a 1.87 g (48%) of the pyrazolone (VId) was isolated. 1H-NMR (DMSO-d6) delta 12.5 (br s, 1H), 10.1 (br s, 1H), 7.62-7.18 (series of multiplets, 4H), 7.10 (s, 1H), 5.87 (s, 1H). MS: 201(M+H)
With hydrogenchloride; In methanol; diethyl ether; chloroform; di-isopropyl ether;
EXAMPLE 1 3-(4-pyridyl)-5-methoxy-pyrazole 300 ml of a solution of approximately 0.5N diazomethane in diethyl ether, freshly prepared, were gradually poured into a 1 liter flask containing 16.1 g of 3-(4-pyridyl)-5-pyrazolone in 150 ml of cold methanol under agitation. The reaction was allowed to take place for 24 hours at room temperature. The solvent was then evaporated until the contents were dry. The residue was dissolved in 50 ml of chloroform, and the solution was filtered to eliminate the remaining quantity of starting pyrazolone which was not reacted. The chloroform phase was then extracted with diluted sodium hydroxide. Diluted hydrochloric acid was added to the aqueous phase to bring the pH to 4, the solution was extracted with chloroform, and then crystallization was carried out in diisopropyl ether. In this manner, 9.1 g (yield 52%) of 3-(4-pyridyl)-5-methoxy pyrazole was obtained with the following characteristics: Melting point M.P.=140 C. IR spectrum (Nujol) v=3500 to 2200, 1610 1575, 1550, 1520, 1400, 1040 cm-1 NMR spectrum delta=3.9 (s,3H), 6.4 (s,1H), 7.7 (2H), 8.6 (2H), 12.7 (1H mobile) ppm (DMSOd6).
EXAMPLE 3 1-benzyl-3-(2'-chloro-5'-nitroanilino)-pyrazolone-(5) SPC7 33.8 g (0.105 mol) of the hydrochloride used in Example 2 were boiled under reflux for 2 hours with 12.2 g (0.1 mol) of benzyl hydrazine in 150 ml of methanol with the addition of 20 ml of glacial acetic acid and 8.2 g (0.1 mol) of anhydrous sodium acetate. The precipitated pyrazolone was suction filtered after cooling. Yield: 15.6 g = 45.5% of the theory M.p.: 232-234C.
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 4 1-phenyl-3-(2'-chloro-4-nitroanilino)-pyrazolone-(5) SPC8 33.8 g (0.105 mol) of ethyl beta-2-chloro-4-nitroanilino-beta-imino-propionate hydrochloride were stirred up with 10.8 g (0.1 mol) of phenyl hydrazine in 50 ml of glacial acetic acid for 60 minutes at a bath temperature of 100C. A thick crystalline paste was obtained which was suction-filtered when cold and washed with ethyl acetate. Pyrazolone yield: 21 g = 63.5% of the theory. M.p.: 245-248C.
Yield
Reaction Conditions
Operation in experiment
61.5%
EXAMPLE 7 1-m-chlorophenyl-3-(2'-chloro-5'-nitroanilino)pyrazolone-(5) SPC11 33.8 g (0.105 mol) of ethyl beta-(2-chloro-5-nitroanilino)beta-imino-propionate hydrochloride were reacted with 14.2 g (0.1 mol) of m-chlorophenyl hydrazine by the method described in Example 4. The pyrazolone was obtained immediately in a yield of 61.5% of the theory.
Yield
Reaction Conditions
Operation in experiment
46%
EXAMPLE 13 1-p-nitrophenyl-3-(2'-trifluoromethyl-4'-chloroanilino)-pyrazolone-(5) SPC17 7.3 g (0.021 mol) of ethyl beta-(2-trifluoromethyl-4-chloroanilino)-beta-imino propionate hydrochloride were reacted with 3.1 g (0.02 mol) of p-nitrophenyl hydrazine by the method described in Example 4. The pyrazolone was formed immediately in a yield of 46% of the theory.
Yield
Reaction Conditions
Operation in experiment
Example 20 1-(3-Nitro-2,4,6-trimethylphenyl)-3-(4-chloroanilino)-5-pyrazolone 26.9 g (0.14 mol) of trimethoxypropionic acid ethyl ester (prepared according to DT-OS 2,042,920) are dissolved in 100 ml of absolute methanol, 7 ml of glacial acetic acid are added and the mixture is heated to the boil. 23.4 g (0.12 mol) of 3-nitro-2,4,6-trimethylphenylhydrazine (prepared according to DT-OS 2,156,913) are introduced in portions into the mixture over the course of 10 minutes. The mixture is stirred for a further 10 minutes at the boil and is allowed to cool whilst stirring. The orange crystals which have precipitated are filtered off, washed with a little methanol and dried (18 hours in vacuo at 50C). 14.4 g of beta-methoxy-beta-(3-nitro-2,4,6-triimethylphenylhydrazino)-acrylic acid ethyl ester of melting point 82 14 83 C are obtained. 16.3 g (0.05 mol) of this compound are well mixed with 6.95 g (0.054mol) of p-chloroaniline and the mixture is stirred with 10.1 ml of glacial acetic acid. The mixture is warmed to 50 C for 4 hours and 50 ml of absolute methanol are then added. The whole is allowed to cool whilst stirring and the crystals are filtered off and rinsed with a little methanol. After drying in vacuo at 70 C, 11.9 g of the pyrazolone, of melting point 263 - 265 C, are obtained.
Yield
Reaction Conditions
Operation in experiment
EXAMPLE V 1-Phenyl-3-(2-chloro-4-nitroanilino)-5-pyrazolone The process of Example I, with addition of toluene, is followed using 2-chloro-4-nitroaniline and phenylhydrazine to provide the corresponding pyrazolone, m.p. 245-8 C.
39
[ 69128-14-9 ]
[ 554-00-7 ]
[ 137-45-1 ]
1-(2,6-Dichloro-4-nitrophenyl)-3-(2,4-dichloroanilino)-5-pyrazolone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene;
EXAMPLE III 1-(2,6-Dichloro-4-nitrophenyl)-3-(2,4-dichloroanilino)-5-pyrazolone The process of Example I, with addition of toluene solvent, is followed using 2,4-dichloroaniline and 2,6-dichloro-4-nitrophenylhydrazine to provide the corresponding pyrazolone, m.p. 229-231 C.
1-(2,4,6-Trichlorophenyl)-3-(4-nitroanilino)-5-pyrazolone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene;
EXAMPLE IV 1-(2,4,6-Trichlorophenyl)-3-(4-nitroanilino)-5-pyrazolone The process of Example I, with addition of toluene, is followed using 4-nitroaniline and 2,4,6-trichlorophenylhydrazine to provide the corresponding pyrazolone, m.p. 300-302 C.
With hydrazine hydrate; In methanol; water; for 1.5h;Reflux;
1.1 3-Hydroxy-1 H-pyrazoleHydrazin hydrate (80% in H2O, 6.7 mL, 1 10 mmol) was slowly added to a solution of (E)-methyl methoxyacrylate (1 1.6 g, 100 mmol) in 10 mL of methanol. The solution was heated to reflux for 90 min upon complete addition. Then, all volatiles were removed under reduced pressure to give the product as a slightly yellow solid (8.2 g, 97.5 mmol, 98% yield) that was sufficiently pure for further transformations.H NMR (DMSO-de, 500 MHz): delta (ppm) = 10.40 (bs, 1 H); 7.35 (d, J = 3.0 Hz, 1 H); 5.44 (d, J = 3.0 Hz, 1 H).13C NMR (DMSO-de, 125 MHz): delta (ppm) = 161.0; 130.1 ; 89.3.Melting point: 137 C.
With hydrazine hydrate; In methanol; at 85℃; for 1.5h;
- Synthesis of lH-pyrazol-3-ol [0226] To a 100 mL round-bottom flask was added methyl (2E)-3-methoxyprop-2- enoate (11.6 g, 99.90 mmol, 1.00 equiv) and methanol (10.0 mL), followed by the addition of hydrazine hydrate (7.8 mL) dropwise with stirring. The resulting solution was stirred for 90 min at 85C, then concentrated under vacuum to afford crude lH-pyrazol-3-ol as a white solid.
With hydrazine hydrate; In methanol; at 85℃; for 1.5h;
[0223] To a 100 mL round-bottom flask was added methyl (2E)-3-methoxyprop-2- enoate (11.6 g, 99.90 mmol, 1.00 equiv) and methanol (10.0 mL), followed by the addition of hydrazine hydrate (7.8 mL) dropwise with stirring. The resulting solution was stirred for 90 min at 85C, then concentrated under vacuum to afford crude lH-pyrazol-3-ol as a white solid.
A solution of 1 ,2-dihydro-pyrazol-3-one (4.50 g, 53.57 mmol) in pyridine (13.5 ml_) was heated to 95C and a solution of acetic anhydride (5.57 ml_, 58.93 mmol) in pyridine (13.5 ml_) was added over 10 minutes and continued heating for additional 3 hours. The reaction mixture was concentrated in vacuo and triturated with 10% ether-pentane to get 1 -acetyl-2, 3-dihydro-1 H-pyrazol-3-one (5.4 g, 80%) as white solid.
71%
With pyridine; at 95℃; for 1.5h;
A solution of <strong>[137-45-1]1,2-dihydro-pyrazol-3-one</strong> (50.0 g, 600 mmol) in pyridine (300 mL) washeated to 95 C. To the solution, a solution of acetic anhydride (61.2 g, 600 mmol) in pyridine(100 mL) was added slowly over 0.5 hour. The reaction was heated for additional hr at 95 C.The reaction mixture was concentrated in vacuo resulting a dark red oil which was triturated withMeOH (150 mL) and filtered to give the 1-acetyl-<strong>[137-45-1]1,2-dihydro-pyrazol-3-one</strong> (54.0 g, yield: 71 %)as a white solid. 1H NMR (300 N'IHz, DMSO-dG): 8 = 10.92 (s, 1H), 8.08 (s, 1H), 5.96 (s, 1H),2. 45 (overlap, 3H).
71%
With pyridine; at 95℃;
A solution of l,2-dihydro-pyrazol-3-one (50.0 g, 600 mmol) in pyridine (300 mL) was heated to 95C. To the solution, a solution of acetic anhydride (61.2 g, 600 mmol) in pyridine (100 mL) was added slowly over 0.5 hour. The reaction was heated for an additional 1 hour at 95C. The reaction mixture was concentrated in vacuo resulting in a dark red oil which was triturated with MeOH (150 mL) and filtered to give l-acetyl-l,2-dihydro-pyrazol-3-one (54.0 g, yield: 71%) as a white solid. 1H NMR (300 MHz, DMSO-r): d = 10.92 (s, 1H), 8.08 (s, 1H), 5.96 (s, 1H), 2.45 (overlap, 3H).
56%
With pyridine; at 95℃; for 1.25h;
A mixture of lH-pyrazol-3(2H)-one (2.5 g, 29.8 mmol, 1 equiv) in pyridine (20.4 mL) was heated to 95C and then charged with a solution of acetic anhydride (4.2 mL, 44.7 mmol, 1.5 equiv) in pyridine (9.6 mL) over a period of 15 mins. The resulting mixture was heated for an additional 1 hour at 95C. Then the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel (eluted with PE/EtOAc = 2/1) to afford the title compound l-acetyl-lH-pyrazol-3(2H)-one as a yellow solid (2.1 g, 56% yield). NMR (DMSO-de) d: 10.95 (br. s., 1H), 8.13 (d, J = 4.0 Hz, 1H), 6.01 (d, J = 4.0 Hz, 1H), 2.48 (s, 3H). LC-MS: m/z 127.1 (M+H)+
With pyridine; at 95℃; for 1.25h;
1-Acetyl-1,2-dihydro-3H-pyrazol-3-one A mixture of 1,2-dihydro-3H-pyrazol-3-one (4.50 g, 26.8 mmol), in pyridine (20.4 mL, 252 mmol) was heated to 95 C. then charged with a solution of acetic anhydride (5.10 mL, 54.0 mmol) in pyridine (9.64 mL, 119 mmol) over a 15 min period. The reaction was heated for an additional 1 h at 95 C. The reaction mixture was concentrated in vacuo resulting in a dark red oil which was triturated with MeOH and filtered resulting in the title compound as a light yellow solid. A 2nd crop of product was isolated from the mother liquors. 1H NMR (400 MHz, DMSO-d6): delta=2.48 (s, 3H) 6.00 (d, J=3.0 Hz, 1H), 8.12 (d, J=3.0 Hz, 1H), 10.95 (br. s., 1H). MS (ES+): m/z 127.23 (100) [MH+]. HPLC: tR=0.82 min (polar-5 min, ZQ3).
With pyridine; at 95℃; for 1h;
Referring to Scheme JJJ, pyrazolone 1-9 is acetylated (e.g., with acetic anhydride and pyridine atelevated temperatures) to provide compound 1-20. The non-acylated nitrogen of 1-20 can engage(R)-oxiran-2-ylmethanol in a Mitsunobu reaction (e.g., with DEAD, PPh3) to afford compound 1-21. The epoxide moiety in 1-21 is opened with a chloride nucleophile (e.g., LiC1), leading to theformation of 1-22. Removal of the acetyl protecting group (e.g,, with aqueous potassium carbonate) allows the formation of 1-23, which is brominated (e.g., with NBS) to provide compound 1-24. Compound 1-24 is methylated (e.g., with Mel and NaH) to provide compound 1-25. Sequential treatment of 1-25 with n-butyl lithium, zinc chloride, TCPC, and ammonium hydroxide provides Intermediate 59. The (5)-enantiomer of Intermediate 59 can be prepared inan analogous fashion using (S)-oxiran-2-ylmethanol in the reaction with 1-20.
<strong>[137-45-1]1H-pyrazole-3(2H)-one</strong> (1.3g, 15mmol), K2CO3 (7.5g, 54mmol) and DMF (60mL) were added to a 100mL vial, heated to 130 C and stirred for 30min.1,3-Dibromopropane (1.9 mL, 19 mmol) was added dropwise and stirring was continued for 2 h.The reaction was completely detected by TLC, and the reaction was quenched by adding 100 mL of H 2 O.Extracted with DCM (30 mL×3) and combined organic phases.Wash with 100 mL of saturated NaCl solution and concentrate.Silica gel column chromatography (DCM/MeOH = 100:1 to 25:1),Obtained 1.8 g of a yellow transparent liquid in a yield of 94%.
56.8%
To a solution of <strong>[137-45-1]<strong>[137-45-1]1,2-dihydropyrazol-3-on</strong>e</strong> (99.5 g, 1184 mmol) in DMF (4000 mL) was added K2CO3 (560.0 g, 4057 mmol), and the mixture was heated at 130 C. for 1 h. Then 1,3-dibromopropane (143.4 mL, 1421 mmol) was added, and the mixture was stirred at 130 C. for 2 h and then concentrated. The resulting residue was partitioned between DCM (2000 mL) and water (2000 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3×1000 mL). The combined organic extracts were dried over Na2SO4 and concentrated to give 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (83.0 g, 56.8%) as a yellow oil. 1H NMR (300 MHz, CDCl3, 30 C.) 2.18-2.11 (2H, m), 4.13-4.05 (2H, m), 4.19-4.16 (2H, m), 5.37-5.37 (1H, m), 7.21-7.20 (1H, m).
51%
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 3h;
2-Dihydro-pyrazol-3-one (4.0 g, 47.6 mmol) and K2CO3 (23.0 g, 166.7 mmol) were heated to 130 C in DMF (80 mL). 1,3-Dibromopropane (1 1.6 g, 57.1 mmol) was added and the mixture was heated for 3 hrs and then concentrated. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was extracted with EA (50 mL) and the combined organic layer was washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel column (PE/EA = 1/2) to give 6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazine (3.0 g, yield: 51%) as a yellow oil. (1308) 20: [00503] SH NMR (400 MHz, CDCb): delta = 7.3 (d, J = 2.0 Hz, i l l ). 5.48 (d, J = 2.0 Hz, I I I ). 4.28 (t, J = 5.2 Hz, 2H), 4.18 (t, J = 6.2 Hz, 2H), 2.29-2.22 (m, 2H).
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 2h;
1H-Pyrazol-3(2H)-one (44, 5.11 g, 60.78 mmol) and potassium carbonate (29.4 g, 212.7 mmol) were heated to 130 C in DMF (275 mL). 1,3-Dibromopropane (7.40 mL, 72.93 mmol) was added and the mixture was heated for 2 h and then concentrated. The residue was partitioned between DCM (200 mL) and water (100 mL) and the layers were separated. The aqueous layer was extracted with DCM (3×100 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (45, 6.0 g) as a brown oil, which was used without further purification.N-Iodosuccinimide (3.79 g, 16.84 mmol) was added portionwise to a solution of crude 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (45, 1.9 g, 15.31 mmol) in acetonitrile (19 mL) at toom temperature and the reaction was stirred for 30 min. The reaction mixture was slowly poured into vigorously stirred water. Sodium thiosulphate solution was added and then the mixture was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (0-2% MeOH/DCM) to give the title compound (46, 1.10 g, 29% for two steps) as a yellow waxy solid
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃;
Referring to Scheme GGG, Intermediate 56 is prepared from compound 1-9. Pyrazolone 1-9 is reacted with 1,3-dibromopropane (e.g., using potassium carbonate as a base at elevated temperatures (e.g., 130 C)) to provide compound 1-10. Bromination of 1-10 (e.g., using NBS) allows the formation of compound 1-11. Treatment of 1-11 with n-BuLi leads to lithium-halogen exchange. The resulting organolithium species is contacted with ZnC12, whereupon treatment of the intermediate with TCPC leads to compound 1-12. Intermediate 56 is obtained by reacting 1-12 with aqueous ammonia.
With hydrazine hydrate; In methanol; at 20℃; for 0.5h;Cooling with ice;
Hydrazine hydrate (3.62 mL, 48.53 mmol) was added dropwise to a cooled (ice bath) solution of methyl propiolate (4.23 mL, 47.58 mmol) in methanol (40 mL). The reaction was allowed to stir for 30 min at room temperature. Brine (10 mL) was added and then the methanol was removed under vacuum. The remaining aqueous layer was extracted with EtOAc (4×75 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield the title compound (44, 3.82 g, 95%) as a cream solid; deltaH (400 MHz, DMSO): 5.44 (1H, d, J 2.27 Hz), 7.35 (1H, d, J 2.23 Hz), 9.50 (1H, br s, NH), 11.45 (1H, br s, NH); deltaC (101 MHz, DMSO): 89.25, 129.71, 160.73; m/z (ES+) 85.04 (100, MH+); HRMS (ESI): MH+, found 85.03951. C3H5N2O requires 85.03964.
78%
With hydrazine hydrate; In methanol; at 0 - 20℃; for 0.5h;
To a solution of methyl propiolate (4.2 mL, 47.58 mmol, 1 equiv) in methanol (40 mL) was added hydrazine hydrate (3.6 mL, 47.58 mmol, 1 equiv) dropwise at 0C. The reaction mixture was allowed to be stirred at room temperature for 30 mins. Brine (10 mL) was added and then methanol was removed under vacuum. The remaining aqueous layer was extracted with EtOAc (4*75 mL). The combined organic phase was dried over anhydrous MgSCri, filtered and concentrated in vacuo to afford the title compound lH-pyrazol-3(2H)- one as a white solid (3.2 g, 78% yield). NMR (400 MHz, DMSO-de) d: 10.68 (br. s., 2H), 7.40 (d, J = 4.0 Hz, 1H), 5.50 (d, J = 4.0 Hz, 1H).
66%
With hydrazine hydrate; In methanol; at 0 - 25℃; for 0.5h;
To a solution of methyl prop-2-ynoate (150 g, 1785.7 mmol) in MeOH (1500 mL) was added hydrazine hydrate (89.2 g, 1784.0 mmol) dropwise at 0 C. The reaction was stirred at r.t. for 30 min. Saturated aqueous sodium chloride (400 mL) was added, and then methanol was removed under vacuum. The aqueous layer was extracted with EtOAc (3×500 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 1,2-dihydropyrazol-3-one (99.5 g, 66%) as a white solid. m/z: ES+[M+H]+ 85.
62%
With hydrazine hydrate; In methanol; at 20℃; for 0.5h;Cooling with ice;
The compound of hydrazine monohydrate (85%, 4.81g, 95.2mrnol) was added dropwise to a cooled (ice bath) solution of 92 (8g, 96.2mmol) in methanol (5OmL). The reaction was allowed to stir for 30 minutes at room temperature, then, the solvent was removed under vacuo. Theremaining aqueous layer was extracted with Et0Ac(5mL5) and the combined organic layerswere dried (MgSO4), filtered and concentrated in vacuo to yield the title product 93 (5g, yield:62?/o)1HNIS?iR (400 MHz, DMSO.-d6): oe5.40 (s, 2H), 7.32 (s, 2 H).
With hydrazine hydrate; In methanol; for 2h;Reflux;
Reference Production Example 1 (0548) A mixture of 21.1 g of methyl 3-methoxyacrylate, 10.0 g of hydrazine hydrate, and 20 mL of methanol was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 11.0 g of 1H-pyrazol-3-ol. 1H-pyrazol-3-ol (0549) (0550) 1H-NMR (DMSO-d6) delta (ppm): 10.22 (1H, s), 7.35 (1H, d, J=2.2 Hz), 5.43 (1H, d, J=2.2 Hz)
11 g
With hydrazine hydrate; In methanol; for 2h;Reflux;
The 21.1g of 3-methoxy-acrylate, and a mixture of 10.0g of hydrazine hydrate in 20mL of methanol was heated under reflux for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure to obtain 11.0 g of 1H- pyrazol-3-ol.
tert-butyl 3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With triethylamine; In dichloromethane; at 20℃; for 6h;
To a solution of 93(2g, 23.Smmoi) in DCM (20m1) was added Boc2O (571g. 26.2mmol) and Et3N (265g, 262mmo]). The mixture was stirred at room temperature for 6 hours. The mixture was extracted with EtOAc (iOOrnLY2) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield the title product 97 (4g. yield: 91%)1HNMR (400 MHz, CDCI3): 31 .54(s, 9H), 571 (s, 2 H), 7.46(s, I H). 7.73(s, I H).
With pyridine; oxygen; copper diacetate; In dichloromethane; at 20℃;
To a solution of 93 (1g. 1i.9rnmol) and 23(3.67g, 17.8mmol) in DCM( Onil) was addedCu(OAc)2 (4.32g. 23. Smmoi) and pyridine(2 .82g. 35. 7mmoi) at room temperature under 02, Themixture was stirred at room temperature overnight, The suspension was filtered through a pad ofCelite and filter cake was washed with DCM(30m1). The combined organic layers were washedwith water and diied over Na2 04. The crude product was purified by silica gel chromatographyto give product 94 (50mg, yield: 1.7%).LCNIS: rn/z, 245.i(M±F1)t
The compound im-8-a (2.85 g, 0.034 mol) was dissolved in pyridine (6 mL), cooled to 0 C., acetic anhydride (3.36 mL, 0.036 mol) And the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed, diethyl ether (30 mL) was added, and the mixture was stirred at room temperature for 16 hours. The resulting solid was filtered and dried to give the title compound im-8 (3.24 g, 76%) as a yellow solid.
To a solution of <strong>[137-45-1]1,2-dihydro-pyrazol-3-one</strong> (500 mg, 5.9 mmol) m NieCN (50 mL) wasadded 1,2-dibromo-ethane (3.3 g, 17.6 mmol) and K2CXh (2.4 g, 17.6 mmol). After bemg stirredat reflux overnight, the reaction mixture was filtered and the filtrate was concentrated in vacuo.The residue was purified by reverse phase HPLC (MeCN m HzO, 5% to 95'%) to give 2,3-dihydro-pyrazolo[5,1-b ]oxazole (260 mg, 40%) as a yellow solid.[00611] 1H NNIR (400 MHz, DMSO-d6): 8 '" 7.27 (s, 1H), 5.37 (d, J '" 1.6 Hz, 1H), 5.06 (t, .J '"8. 0 Hz, 2H), 4.23 (t, J '" 8. 0 Hz, 2H).
rac-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
To a solution of 2-methyl-propane-1,3-diol (1 g, 11 1 mmol) and TEA (4.5 g, 44.4mmol) in THF (30 mL), was added MsCl (2.8 g, 24.4 mmol) slowly with ice-cooling under N2.The reaction was stirred at room temperature for 1 hr and filtered. The filtrate was concentratedto give a colorless oil. A mixture of this oil, <strong>[137-45-1]1,2-dihydro-pyrazol-3-one</strong> (993 mg, 11 1 mmol) andK2C03 (6.1 g, 44.4 mmol) m DMF (40 mL) was heated to 80 C for 12 hrs. The reaction wascooled and partitioned between EA (100 mL) and water (200 mL) and the layers were separated.The organic layer was washed with water (80 mL) and brme (50 mL), dned over Na2.S04 andconcentrated. The residue was purified by silica gel column (PE/EA '" 2/1) to give rac-6-methy 1-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (500 mg, yield: 33~~) as a white solid.[00700] 1B NNIR (300 MHz, CDCh): 5 '" 7.31 (s, 1B), 5.47 (s, IB), 4.27-4.23 (m, 2B), 3.87-3.68 (m, 2H), 2.47-2.45 (m, 1H), 1.23-1.09 (m, 3H). MS: m/z 139.0 (M+H'}
5',7'dihydrospiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
To a solution of(I-hydroxymethyl-cyclopropyl)-methanol (1.53 g, 15 mmol) and TEA(6. 1 g, 60 mmol) in THF (45 mL), was added MsCl (3.8 g, 33 mmol) slowly with ice-coolingunder N2. After being stirred at room temperature for 1 hr, the reaction vas partitioned betweenEA (500 mL) and water (100 mL). The organic layer was washed vv-ith brine (100 mL), driedover Na2S04 and concentrated to give a colorless oil. A mixture of this oil, 1 ,2-dihydro-pyrazol-3-one ( l .3 g, 15 mmol) and K2C03 (8.3 g, 60 mmol) in DlVIF (60 mL) was heated to 80 Covernight. The reaction was cooled and partitioned between EA (120 mL) and water (300 mL).The organic layer was washed with water (100 mL) and brine (80 mL), dried over Na2S04 andconcentrated. The residue was purified by reverse phase HPLC (MeCN/EbO) to give 5',7'dihydrospiro[cyclopropane-1,6'-pyrazolo[5,1-b][l,3]oxazine] (380 mg, yield: l7~o) as a whitesolid.[00713] 1H NMR (300 MHz, CDCh): () '" 7.33 (d, J "' 1.8 Hz, 1 H), 5.52 (d, J '" 1.8 Hz, 1 H),3.99 (s, 4H), 0.81-0.49 (m, 4H). MS: m/z 151.0 (M+H').
Referring to Scheme KKK, cyclopropane-1,1-diyldimethanol is mesylated (e.g., with MsC1 and TEA). Treatment of the ensuing mesylate with pyrazolone 1-9 affords compound 1-26 (e.g., usingpotassium carbonate as the base and DMF as the solvent). Compound 1-26 is brominated (e.g., with NBS) to afford 1-27 which is reacted sequentially with n-butyl lithium, zinc chloride, and TCPC to furnish compound 1-28. Intermediate 60 is obtained by reacting compound 1-28 with aqueous ammonia.
1-tosyl-5',7'dihydrospiro[azetidine-3,6'-pyrazolo[5,1-b][1,3]oxazine][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 16h;
To a solution of 3,3-bis-bromomethyl-1-(toluene-4-sulfonyl)-azetidine (4.2 g, 10.6mmol) and <strong>[137-45-1]1,2-dihydro-pyrazol-3-one</strong> (0.89 g, 10.6 mmol) in Dl'VIF (50 mL) was added K2C03(3.7 g, 26.5 mmol). After being stirred at 130 C for 16 hrs, the reaction was cooled down andquenched with the addition ofEA (1 00 mL) and water (1 00 mL). The organic layer wasseparated. The aqueous layer was extracted with EA ( 100 mL). The organic layers werecombined, washed with brine (80 mL), dried over Na2S04 and concentrated in vacuo. Theresidue was purified by silica gel column (PE/EA '" 1/1) to g1ve 1-tosyl-5', 7'dihydrospiro[azetidine-3,6'-pyrazolo[5,1-b][l,3]oxazine] (1.4 g, yield: 42~~) as a white solid.MS: m/z 320 (M+H').
tert-butyl (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;
A mixture of 2-((tert-butoxycarbony l)ammo )propane-I ,3-diy l dimethanesulfonate (3. 9g, 11.2 mmol), 1 ,2-dihydro-pyrazol-3-one (945 mg, 11.2 mmol) and K2C03 (5.4 g, 39.3 mmol) in DNIF (30 mL) was heated to 80 C for 12 hrs. The reaction was cooled and partitionedbetween EA (150 mL) and water (200 mL). The organic layer was washed with water (80 mL)and bnne (50 mL), dned over Na2S04 and concentrated. The residue was purified by silica gelcolumn (PE/EA '" 1/1) to give tert-butyl (6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazin-6-yl)carbamate (975 mg, yield: 13%) as a white solid.[00734] 1H NNIR (300 MHz, CDCh): 5 '" 7.37 (d, J '" 1.2 Hz, IH), 5.55 (d, J "' 1.5 Hz, 1H),5.14-5.04 (m, 1H), 4.43-4.12 (m, 5H), 1.46 (s, 9H). MS: mlz 240.1 (M+H+).
With potassium carbonate; In N,N-dimethyl-formamide;Heating;
Referring to Scheme LLL, the amino group in diol 1-29 is protected with Boc2O to provide compound 1-30 which is mesylated (e.g., with MsC1 and TEA) to afford compound 1-31. Compound 1-31 is subjected to a double nucleophilic substitution with pyrazolone 1-9, providing1-32, which is brominated (e.g., with NBS) to afford compound 1-33. Sequential treatment of 1-33 with n-butyl lithium, zinc chloride, and TCPC provides compound 1-34. Intermediate 61 is obtained when 1-34 is reacted with aqueous ammonia.
6-methylene-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;
A m1xture of <strong>[137-45-1]1,2-dihydro-pyrazol-3-one</strong> (10.42 g, 0.124 mol) and K2.C03 (42.8 g, 0.31mol) m DMF (700 mL) was heated to 100 C. 3-Chloro-2-chloromethyl-propene (15.5 g, 0.124mol) was added and the mixture was stirred at 1 00 C for 16 hrs. The sol vent was removed invacuo. The residue was partitioned between EA (200 mL) and fbO (500 mL). The aqueous layerwas extracted with EA (200 mL). The combined organic layer was washed with brine (I 00 mL),dried over Na2S04 and concentrated. The residue was purified by silica gel column (PE/EA =1/1) to give 6-methylene-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.7 g, yield: 10%) as ayellow oil.[00743] 1H NlVIR (300 rviHz, CDCb): 8 = 7.34 (s, 1H), 5.51 (s, 1H), 5.39 (s, 2H), 4.80 (s, 2H),4.63 (s, 2H). MS: m/z 137.1 (M+H'}
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;
Referring to Scheme MMM, bis-chloride 1-35 is reacted with pyrazolone 1-9 to yield compound1-36. Hydroboration-oxidation of 1-36 provides compound 1-37, whereupon the primary alcoholis converted into an azido group (e.g., with DPPA and DBU). The azide moiety in the resulting 1-38 is then reduced (e.g., with Pd/C, H2); and the ensuing amino group is protected with Boc2O toafford 1-39. Compound 1-39 is brominated to provide 1-40. Sequential treatment of 1-40 with nbutyl lithium, zinc chloride, and TCPC affords compound 1-41. Intermediate 62 is obtained by treating 1-41 with aqueous ammonia.
2-isopropoxypropane-1,3-diyl dimethanesulfonate[ No CAS ]
6-isopropoxy-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.1 g
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;
A mixture of2-isopropoxypropane-1,3-diyl dimethanesulfonate (crude, "~18.7 mmol),<strong>[137-45-1]1,2-dihydro-pyrazol-3-one</strong> (1 6 g, 18.7 mmol) and K2C03 (7.7 g, 56.0 mmol) in DTVIF (40 mL)was heated to 1 00 C for 16 hrs. The reaction was cooled and pmiitioned between EA ( 150 mL)and water (200 mL) and the layers were separated. The organic layer was vv·ashed with water (80mL) and brine (50 mL), dried over Na2S04 and concentrated. The residue was purified by silicagel column (PE/EA = 1/2) to give 6-isopropoxy-6, 7-dihydro-5H-pyrazolo[5, 1-b ][1,3]oxazine(2.1 g, yield: 88%) as a white solid.[00795] 1HNl1R(300TVIHz, CDCh): 8 = 7.33 (s, IH), 5.49 (s, lH), 4.31-3.84 (m, 5H), 3 84-3.80 (m, lH), 1.22-118 (m, 6H). MS: m/z 183.3 (M+H').
rac-6-ethyl-6,7-dihydro-5Hpyrazolo[5,1-b][1,3]oxazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
650 mg
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;
A mixture of2-ethylpropane-1,3-diyl dimethanesulfonate (crude), <strong>[137-45-1]1H-pyrazol-3(2H)one</strong>(750 mg, 8.9 mmol) and K2C03 (4.3 g, 31.2 mmol) in D:N1:F (40 mL) was heated at 100 Cfor 16 hrs. The reaction mixture was partitioned between EA/}bO (80 mL /200 mL) and thelayers were separated. The aqueous layer was extracted with EA (80 mL x3) and the combinedorganic layer was washed with brine (50 mL), dried over Na2S04 and concentrated. The residuewas purified by silica gel column (PE/EA = 3/1) to give rac-6-ethyl-6,7-dihydro-5Hpyrazolo[5,l-b][l,3]oxazine (650 mg, yield: 48~~) as a colorless oil.[00886] 1H NrviR (300 lVlliz, CDCh): 8 = 7.32 (d, J = 1.5 Hz, lH), 5.48 (d, J = 1.5 Hz, lH),4.34-4.26 (m, 2H), 3.95-3.87 (m, 1H), 3.81-3.73 (m, IH), 2.30-2.19 (m, lH), 1.60-1.40 (m, 2H),1.05 (t, J = 7.5 Hz, 3H
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;
Referring to Scheme QQQ, diester compound 1-53 is reduced to give rise to diol 1-54 which is mesylated (e.g., with MsCl) to provide 1-55. Treatment of 1-55 with pyrazolone 1-9 affords bicyclic compound 1-56. Exposure of 1-56 to C1SO3H (e.g., at elevated temperatures) provides 1- 57, whereupon treatment with aqueous ammonia affords Intermediate 66. Chiral separation ofIntermediate 66 affords Intermediate 66a and 66b.
6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 24h;
1,2-Dihydro-pyrazol-3-one (25.0 g, 297.6 mmol) and K2C03 (144.0 g, 1041.7 mmol)were heated to 120 C in DMF (700 mL). 1 ,3-Dibromo-2,2-dimethyl-propane (82.0 g, 357.1mmol) was added and the mixture was heated for 24 hrs. The solvent was removed in vacuo. Theresidue was partitioned between EA/1-bO (200 mL /500 mL) and the layers were separated. Theaqueous layer was extracted with EA (200 mL) and the combined orgamc layer was washed withbrine (100 mL), dried over Na2S04 and concentrated. The residue was cooled to 5 C and washedwith PE (100 mL) to give 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (14.0 g,yield: 31%) as a yellow solid.1HN:MR (300 MHz, CDCh): 5 '" 7.32 (s, lH), 5.48 (s, IH), 3.87 (s, 2H), 3.84 (s, 2H),1.13 (s, 6H).
rac-6-(tetrahydropyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With potassium carbonate; In N,N-dimethyl-formamide;
A mixture of 2-(2-brmno-1-brmnomethyl-ethoxy)-tetrahydro-pyran (17 g, 56.3 mmol),1 ,2-dihydro-pyrazol-3-one ( 4 g, 47 rmnol) and K2C03 (23 g, 165 mmol) in DJIF (250 rnL) wasstirred at 1 00 C overmght The solvent was removed under reduced pressure. The residue waspartitioned between EA (200 mL) and water (200 ml). The aqueous phase was extracted with EA(200 ml). The orgamc layers were cmnbined, washed with water (100 mL) and brine (100 rnL),dried over Na2S04 and concentrated. The residue was purified by silica gel column (EA) to gtve6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazme (4.9 g, yield: 46%) asa yellow oiL[00549] 1H NJIIR (300 MHz, DMSO-d6): 8 '" 7.34 (s, lH), 5.51 (s, 1H), 4.89-4.83 (m, 1H),4.36-4.24 (m, 4H), 3.93-3.88 (m, 1H), 3.59-3.54 (m, 1H), 1.79-1.69 (m, 3H), 1.65-1.51 (m, 4H).MS: m/z 224.9 (M+fr).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
Referring to Scheme HHH, pyrazolone 1-9 is reacted with 2-((1,3-dibromopropan-2- yl)oxy)tetrahydro-2H-pyran to produce compound 1-13 which is brominated (e.g., with NBS) toprovide compound 1-14. Sequential treatment of compound 1-14 with n-butyl lithium, zinc chloride, and TCPC affords compound 1-15. The reaction between 1-15 and aqueous ammonia then provides 1-16. The THP protecting group in 1-16 is removed with HC1, affording Intermediate 57.
5,6,7,8-tetrahydro-4-oxa-1,8a-diazaazulene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 16h;
1 ,2-Dihydro-pyrazol-3-one (3.0 g, 35.7 mmol) and K£03 (17.0 g, 125.0 mmol) wereheated to 130 C in D:N1:F (100 mL). 1,4-Dibromo-butane (9.3 g, 42.9 mmol) was added and themixture was heated for 16 hrs. The solvent was removed in vacuo. The residue was partitionedbetween EA/H20 (50 mL /80 mL) and the layers were separated. The aqueous layer wasextracted with EA (50 mL) and the combined organic layers were washed with brine (50 mL),dried over Na2S04 and concentrated. The residue was purified by silica gel column (PE/EA =1/1) to give 5,6,7,8-tetrahydro-4-oxa-1,8a-diaza-azulene (1.3 g, yield: 27%) as a colorless oil.[00560] 1H NlVIR (300 MHz, CDCb): 8 = 7.24 (d, J = 1.5 Hz, lH), 5.69 (d, J = 1.5 Hz, IH),4.25-4.20 (m, 2H), 4.06 (t, J = 5.1 Hz, 2H), 2.07-2.03 (m, 2H), 1.91-1.84 (m, 2H).
With sodium hydroxide; In toluene; at 30 - 113℃; for 4.5h;
After reducing the solution containing pyrazol in step (2) to 30 ° C, adding 45.18 g of toluene, stirring for 0.5 h, increasing the temperature of the mixture and refluxing the water to a moisture content of 0.08percent in the mixture. The temperature of the mixture was lowered to 40 ° C, 58.01 g (99percent, 0.3 mol) of p-bromochlorobenzene and 16.16 g (99percent, 0.4 mol) of sodium hydroxide were added, and the temperature of the mixture was raised to 110 ° C. After refluxing for 4 hours, the mixture was detected by liquid phase method multiple times. When the pyrazole peak disappeared, the reaction was stopped. After the temperature of the mixed solution was lowered to 40 ° C, 50 g of water was added to the mixture, and the mixture was dropped. Add hydrochloric acid to the pH of the mixture = 3, then raise the temperature of the mixture to 95 ° C, distill off the toluene, finally reduce the temperature of the mixture to 30 ° C, and suction to obtain 1-(4-chlorophenyl)-3-pyrazolol.Using this method, 31.96 g of 1-(4-chlorophenyl)-3-pyrazol was obtained in content of 97percent, yield 80percent.
With hydrazine hydrate; In methanol;Cooling with ice;
Under the ice bath,Hydrazine hydrate in a 100 mL single-mouth bottle(0.75 mL, 15 mmol) A solution of ethyl propiolate (1.5 mL, 15 mmol) in methanol (15 mL).TLC detection, the raw material reaction is complete, spin dry methanol,A yellow viscous liquid was obtained and the next step was taken directly.
2-((1H-pyrazol-5-yl)oxy)-1-(2-chlorophenyl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.08 g
Step 1 : lH-pyrazol-3(2H)-one (1 g, 11.8 mmol) was dissolved in DMF (10 mL) and cesium carbonate (4.20 g, 12.9 mmol) was added. The reaction mixture was heated to 50 C. After 5 minutes, 2-bromo-l-(2-chlorophenyl)ethanone (2.35 g, 10.1 mmol) in DMF (12 mL) was slowly added over 10 min. The reaction mixture was stirred for 1 hour at 50 C. After cooling to RT, the mixture was partitioned between EtOAc (50mL) and saturated NaHCO-, (20 mL). The aqueous layer was washed with EtOAc and the combined organics were washed with water, washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0-40% EtOAc) to give 2-(( l//-pyrazol-5-yl)oxy)- l -(2-chl orophenyl)ethanone (1.08 g, 4.57 mmol) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) d ppm 5.25 (s, 2 H) 5.66 (t, J=2.20 Hz, 1 H) 7.43 - 7.48 (m, 1 H) 7.49 (t, J=l .95 Hz, 1 H) 7.51 - 7.57 (m, 2 H) 7.72 (d, J=8.06 Hz, 1 H) 11.88 (br s, 1 H).
tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6%
To a solution of l/7-pyrazol-3(2/ )-one (20.0 g, 238 mmol) in DCM (300 mL) was added triethylamine (37 mL, 267 mmol) at 0C. After 10 minutes, Boc20 (57.11 g, 262 mmol) in DCM (100 mL) was added drop-wise. After addition, the reaction was warmed to room temperature and was allowed to stir for 16 hours. The reaction was concentrated under reduced pressure and the crude residue was dissolved in water (100 mL). The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layers were dried over Na2S04, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give /c/Z-butyl 3 -hydroxy- 1 //-pyrazole- 1 -carboxylate (2.8 g, yield: 6%) as a yellow solid. 1H NMR (400 MHz, DMSO-i): d = 10.92 (s, 1H), 7.97 (d, j= 3.2 Hz, 1H), 5.89 (d, j= 2.8 Hz, 1H), 1.53 (s, 9H).
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